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- EMDB-23920: Cryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D r... -

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Basic information

Entry
Database: EMDB / ID: EMD-23920
TitleCryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Map dataCryo-EM map of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Sample
  • Complex: 1:1 c-MET I/HGF I complex
    • Protein or peptide: Hepatocyte growth factor
    • Protein or peptide: Hepatocyte growth factor receptor
Keywordsc-MET / HGF / receptor tyrosine kinase / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / endothelial cell morphogenesis / MET Receptor Activation / MET interacts with TNS proteins / pancreas development / semaphorin receptor activity ...regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / endothelial cell morphogenesis / MET Receptor Activation / MET interacts with TNS proteins / pancreas development / semaphorin receptor activity / MET receptor recycling / cellular response to hepatocyte growth factor stimulus / MET activates PTPN11 / hepatocyte growth factor receptor signaling pathway / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / positive regulation of endothelial cell chemotaxis / MET activates PI3K/AKT signaling / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive regulation of DNA biosynthetic process / negative regulation of release of cytochrome c from mitochondria / positive chemotaxis / chemoattractant activity / positive regulation of osteoblast differentiation / semaphorin-plexin signaling pathway / epithelial to mesenchymal transition / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / MET activates RAS signaling / MECP2 regulates neuronal receptors and channels / platelet alpha granule lumen / Interleukin-7 signaling / cell surface receptor protein tyrosine kinase signaling pathway / liver development / basal plasma membrane / negative regulation of autophagy / excitatory postsynaptic potential / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / growth factor activity / cell chemotaxis / receptor protein-tyrosine kinase / Negative regulation of MET activity / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / Platelet degranulation / PIP3 activates AKT signaling / mitotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / protein phosphatase binding / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / signaling receptor complex / cell surface receptor signaling pathway / postsynapse / positive regulation of cell migration / signaling receptor binding / negative regulation of apoptotic process / cell surface / positive regulation of transcription by RNA polymerase II / : / extracellular region / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / divergent subfamily of APPLE domains / : / Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily ...Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / divergent subfamily of APPLE domains / : / Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / Plexin repeat / Plexin repeat / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / IPT/TIG domain / ig-like, plexins, transcription factors / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Peptidase S1, PA clan, chymotrypsin-like fold / Protein kinase domain profile. / Protein kinase domain / Peptidase S1, PA clan / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Hepatocyte growth factor receptor / Hepatocyte growth factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsUchikawa E / Chen ZM
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis of the activation of c-MET receptor.
Authors: Emiko Uchikawa / Zhiming Chen / Guan-Yu Xiao / Xuewu Zhang / Xiao-Chen Bai /
Abstract: The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic ...The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor.
History
DepositionMay 1, 2021-
Header (metadata) releaseJun 9, 2021-
Map releaseJun 9, 2021-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mo8
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23920.png

Downloads & links

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Map

FileDownload / File: emd_23920.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 270 pix.
= 291.6 Å		1.08 Å/pix.
x 270 pix.
= 291.6 Å		1.08 Å/pix.
x 270 pix.
= 291.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.017888956 - 0.044926252
Average (Standard dev.)0.00009532235 (±0.001854064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions270270270
Spacing270270270
CellA=B=C: 291.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z270270270
origin x/y/z0.0000.0000.000
length x/y/z291.600291.600291.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ192192192
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS270270270
D min/max/mean-0.0180.0450.000

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Supplemental data

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Sample components

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Entire : 1:1 c-MET I/HGF I complex

EntireName: 1:1 c-MET I/HGF I complex
Components
  • Complex: 1:1 c-MET I/HGF I complex
    • Protein or peptide: Hepatocyte growth factor
    • Protein or peptide: Hepatocyte growth factor receptor

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Supramolecule #1: 1:1 c-MET I/HGF I complex

SupramoleculeName: 1:1 c-MET I/HGF I complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Hepatocyte growth factor

MacromoleculeName: Hepatocyte growth factor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.249828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWVTKLLPAL LLQHVLLHLL LLPIAIPYAE GQRKRRNTIH EFKKSAKTTL IKIDPALKIK TKKVNTADQC ANRCTRNKGL PFTCKAFVF DKARKQCLWF PFNSMSSGVK KEFGHEFDLY ENKDYIRNCI IGKGRSYKGT VSITKSGIKC QPWSSMIPHE H SFLPSSYR ...String:
MWVTKLLPAL LLQHVLLHLL LLPIAIPYAE GQRKRRNTIH EFKKSAKTTL IKIDPALKIK TKKVNTADQC ANRCTRNKGL PFTCKAFVF DKARKQCLWF PFNSMSSGVK KEFGHEFDLY ENKDYIRNCI IGKGRSYKGT VSITKSGIKC QPWSSMIPHE H SFLPSSYR GKDLQENYCR NPRGEEGGPW CFTSNPEVRY EVCDIPQCSE VECMTCNGES YRGLMDHTES GKICQRWDHQ TP HRHKFLP ERYPDKGFDD NYCRNPDGQP RPWCYTLDPH TRWEYCAIKT CADNTMNDTD VPLETTECIQ GQGEGYRGTV NTI WNGIPC QRWDSQYPHE HDMTPENFKC KDLRENYCRN PDGSESPWCF TTDPNIRVGY CSQIPNCDMS HGQDCYRGNG KNYM GNLSQ TRSGLTCSMW DKNMEDLHRH IFWEPDASKL NENYCRNPDD DAHGPWCYTG NPLIPWDYCP ISRCEGDTTP TIVNL DHPV ISCAKTKQLR VVNGIPTRTN IGWMVSLRYR NKHICGGSLI KESWVLTARQ CFPSRDLKDY EAWLGIHDVH GRGDEK CKQ VLNVSQLVYG PEGSDLVLMK LARPAVLDDF VSTIDLPNYG CTIPEKTSCS VYGWGYTGLI NYDGLLRVAH LYIMGNE KC SQHHRGKVTL NESEICAGAE KIGSGPCEGD YGGPLVCEQH KMRMVLGVIV PGRGCAIPNR PGIFVRVAYY AKWIHKII L TYKVPQS

UniProtKB: Hepatocyte growth factor

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Macromolecule #2: Hepatocyte growth factor receptor

MacromoleculeName: Hepatocyte growth factor receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 155.720625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL AKSEMNVNMK YQLPNFTAET PIQNVILHEH HIFLGATNYI YVLNEEDLQK VAEYKTGPV LEHPDCFPCQ DCSSKANLSG GVWKDNINMA LVVDTYYDDQ LISCGSVNRG TCQRHVFPHN HTADIQSEVH C IFSPQIEE ...String:
MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL AKSEMNVNMK YQLPNFTAET PIQNVILHEH HIFLGATNYI YVLNEEDLQK VAEYKTGPV LEHPDCFPCQ DCSSKANLSG GVWKDNINMA LVVDTYYDDQ LISCGSVNRG TCQRHVFPHN HTADIQSEVH C IFSPQIEE PSQCPDCVVS ALGAKVLSSV KDRFINFFVG NTINSSYFPD HPLHSISVRR LKETKDGFMF LTDQSYIDVL PE FRDSYPI KYVHAFESNN FIYFLTVQRE TLDAQTFHTR IIRFCSINSG LHSYMEMPLE CILTEKRKKR STKKEVFNIL QAA YVSKPG AQLARQIGAS LNDDILFGVF AQSKPDSAEP MDRSAMCAFP IKYVNDFFNK IVNKNNVRCL QHFYGPNHEH CFNR TLLRN SSGCEARRDE YRTEFTTALQ RVDLFMGQFS EVLLTSISTF IKGDLTIANL GTSEGRFMQV VVSRSGPSTP HVNFL LDSH PVSPEVIVEH TLNQNGYTLV ITGKKITKIP LNGLGCRHFQ SCSQCLSAPP FVQCGWCHDK CVRSEECLSG TWTQQI CLP AIYKVFPNSA PLEGGTRLTI CGWDFGFRRN NKFDLKKTRV LLGNESCTLT LSESTMNTLK CTVGPAMNKH FNMSIII SN GHGTTQYSTF SYVDPVITSI SPKYGPMAGG TLLTLTGNYL NSGNSRHISI GGKTCTLKSV SNSILECYTP AQTISTEF A VKLKIDLANR ETSIFSYRED PIVYEIHPTK SFISGGSTIT GVGKNLNSVS VPRMVINVHE AGRNFTVACQ HRSNSEIIC CTTPSLQQLN LQLPLKTKAF FMLDGILSKY FDLIYVHNPV FKPFEKPVMI SMGNENVLEI KGNDIDPEAV KGEVLKVGNK SCENIHLHS EAVLCTVPND LLKLNSELNI EWKQAISSTV LGKVIVQPDQ NFTGLIAGVV SISTALLLLL GFFLWLKKRK Q IKDLGSEL VRYDARVHTP HLDRLVSARS VSPTTEMVSN ESVDYRATFP EDQFPNSSQN GSCRQVQYPL TDMSPILTSG DS DISSPLL QNTVHIDLSA LNPELVQAVQ HVVIGPSSLI VHFNEVIGRG HFGCVYHGTL LDNDGKKIHC AVKSLNRITD IGE VSQFLT EGIIMKDFSH PNVLSLLGIC LRSEGSPLVV LPYMKHGDLR NFIRNETHNP TVKDLIGFGL QVAKGMKYLA SKKF VHRDL AARNCMLDEK FTVKVADFGL ARDMYDKEYY SVHNKTGAKL PVKWMALESL QTQKFTTKSD VWSFGVLLWE LMTRG APPY PDVNTFDITV YLLQGRRLLQ PEYCPDPLYE VMLKCWHPKA EMRPSFSELV SRISAIFSTF IGEHYVHVNA TYVNVK CVA PYPSLLSSED NADDEVDTRP ASFWETS

UniProtKB: Hepatocyte growth factor receptor

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 25787
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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